tbuckley/cabot-search huggingface dataset:
Prognostic factors influencing progression-free survival in HER2 positive metastatic breast cancer patients who treated with lapatinib and capecitabine combination.
Authors: Izzet Dogan, Nail Paksoy, Naziye Ak, Sezai Vatansever, Pinar Saip, Adnan Aydiner
Journal: Journal of Clinical Oncology (2022)

e13031 Background: Her2 positivity is detected in about 20% of breast cancer patients. After trastuzumab-based therapy, lapatinib and capecitabine combination is a treatment option in HER2-positive metastatic patients. The study aimed to evaluate the prognostic factors in HER2 positive metastatic breast cancer patients treated lapatinib and capecitabine combination. Methods: We evaluated data of the HER2 positive metastatic breast cancer patients who were treated with lapatinib and capecitabine retrospectively. The patients' clinical, pathological, and treatment features were recorded from the hospital database. Kaplan Meier and Cox regression analysis were used for survival analysis. Results: 102 patients were included in the study. The median age was 47 (range, 24-87), and 99 (97.1%) patients were female. The number of de-novo metastatic patients was 44 (43.1%). The most common metastatic sites were bone (62.4%), brain (58.6%), liver (35.6%), and lung (34.7%), respectively. All patients were previously treated with trastuzumab-based chemotherapy. 44 (44.1%) patients received hormonotherapy (tamoxifen or aromatase inhibitor), and 23 (22.5%) patients palliative radiotherapy. Complete response was 8.2%, partial response 32%, and stable disease 25.8% with lapatinib and capecitabine combinations. At a median follow of 11.6 months, progression-free survival was 8 (95% CI, 5.1-10.8) months. In multivariate analysis, age (p = 0.020), de-novo metastatic disease (p = 0.028), and endocrine therapy (p = 0.020) were statistically significant prognostic factors for progression-free survival. However, history of breast surgery (p = 0.060), number of chemotherapy used with trastuzumab (p = 0.338), number of metastatic sites (p = 0.257), and palliative radiotherapy (p = 0.394) were not significant. Conclusions: We showed real-life outcomes of the lapatinib and capecitabine combination in metastatic HER2-positive breast cancer patients. Also, we detect that being under age 50 years, de-novo metastatic disease, and hormone-negative tumor were poor prognostic factors of progression-free survival.
Deciphering the mechanistic role of PBRM1 loss in inflammatory and morphogenic signalling within the tumour microenvironment of clear cell renal cell carcinoma
Authors: N. Klümper, J. Linxweiler, K.N. Tran, P. Zeuschner, S. Ng, S. Leonardelli, J. Albrecht, S. Rieck, A. Bamarni, T.T. Lindenberg, B. Odermatt, G. Kristiansen, M. Ritter, J. Ellinger, A. Alajati, B.K. Fleischmann, K. Junker, M. Toma, M. Hölzel
Journal: European Urology (2022)
The use of abdominal drain after robot-assisted surgery in urology: Impact on postoperative pain
Authors: L. Nocera, G. Basile, A. Larcher, G. Colandrea, S. Scuderi, F. Barletta, A. Crescenti, C. Mattioli, P. Karakiewicz, A. Mottrie, M. Moschini, A. Stabile, G. Gandaglia, U. Capitanio, A. Salonia, A. Briganti, F. Montorsi
Journal: European Urology (2022)
A Healthy Lifestyle in Men at Increased Genetic Risk for Prostate Cancer
Authors: Anna Plym, Yiwen Zhang, Konrad H. Stopsack, Bénédicte Delcoigne, Fredrik Wiklund, Christopher Haiman, Stacey A. Kenfield, Adam S. Kibel, Edward Giovannucci, Kathryn L. Penney, Lorelei A. Mucci
Journal: European Urology (2022)

Prostate cancer is the most heritable cancer. There is a need to identify possible modifiable factors for men at an increased risk of prostate cancer due to genetic factors. To examine whether men at an increased genetic risk of prostate cancer can offset their risk of disease or disease progression by adhering to a healthy lifestyle. We prospectively followed 12 411 genotyped men in the Health Professionals Follow-up Study (1993–2019) and the Physicians' Health Study (1983–2010). Genetic risk of prostate cancer was quantified using a polygenic risk score (PRS). A healthy lifestyle was defined by healthy weight, vigorous physical activity, not smoking, and a healthy diet. Overall and lethal prostate cancer events (metastatic disease/prostate cancer–specific death) were analyzed using time-to-event analyses estimating hazard ratios (HRs) and lifetime risks. During 27 yr of follow-up, 3005 overall prostate cancer and 435 lethal prostate cancer events were observed. The PRS enabled risk stratification not only for overall prostate cancer, but also for lethal disease with a four-fold difference between men in the highest and lowest quartiles (HR, 4.32; 95% confidence interval [CI], 3.16–5.89). Among men in the highest PRS quartile, adhering to a healthy lifestyle was associated with a decreased rate of lethal prostate cancer (HR, 0.55; 95% CI, 0.36–0.86) compared with having an unhealthy lifestyle, translating to a lifetime risk of 1.6% (95% CI, 0.8–3.1%) among the healthy and 5.3% (95% CI, 3.6–7.8%) among the unhealthy. Adhering to a healthy lifestyle was not associated with a decreased risk of overall prostate cancer. Our findings suggest that a genetic predisposition for prostate cancer is not deterministic for a poor cancer outcome. Maintaining a healthy lifestyle may provide a way to offset the genetic risk of lethal prostate cancer. This study examined whether the genetic risk of prostate cancer can be attenuated by a healthy lifestyle including a healthy weight, regular exercise, not smoking, and a healthy diet. We observed that adherence to a healthy lifestyle reduced the risk of metastatic disease and prostate cancer death among men at the highest genetic risk. We conclude that men at a high genetic risk of prostate cancer may benefit from adhering to a healthy lifestyle.
Recurrent noncoding somatic and germline <i>WT1</i> variants converge to disrupt MYB binding in acute promyelocytic leukemia
Authors: Huan Song, Yabin Liu, Yun Tan, Yi Zhang, Wen Jin, Li Chen, Shishuang Wu, Jinsong Yan, Junmin Li, Zhu Chen, Saijuan Chen, Kankan Wang
Journal: Blood (2022)

Genetic alternations can occur at noncoding regions, but how they contribute to cancer pathogenesis is poorly understood. Here, we established a mutational landscape of cis-regulatory regions (CREs) in acute promyelocytic leukemia (APL) based on whole-genome sequencing analysis of paired tumor and germline samples from 24 patients and epigenetic profiling of 16 patients. Mutations occurring in CREs occur preferentially in active enhancers bound by the complex of master transcription factors in APL. Among significantly enriched mutated CREs, we found a recurrently mutated region located within the third intron of WT1, an essential regulator of normal and malignant hematopoiesis. Focusing on noncoding mutations within this WT1 intron, an analysis on 169 APL patients revealed that somatic mutations were clustered into a focal hotspot region, including one site identified as a germline polymorphism contributing to APL risk. Significantly decreased WT1 expression was observed in APL patients bearing somatic and/or germline noncoding WT1 variants. Furthermore, biallelic WT1 inactivation was recurrently found in APL patients with noncoding WT1 variants, which resulted in the complete loss of WT1. The high incidence of biallelic inactivation suggested the tumor suppressor activity of WT1 in APL. Mechanistically, noncoding WT1 variants disrupted MYB binding on chromatin and suppressed the enhancer activity and WT1 expression through destroying the chromatin looping formation. Our study highlights the important role of noncoding variants in the leukemogenesis of APL.
IMG-01. Quantitative Direct Sodium (23Na) MRI in Pediatric Gliomas
Authors: Aashim Bhatia
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: The treatment of pediatric gliomas is typically assessed with proton (1H) MRI, which can have limitations. 23Na MRI has been shown in adult brain tumors to measure intra-tumoral total sodium concentration as a correlate of tumor proliferation. 23Na MRI sodium studies in pediatric patients are lacking. PURPOSE: (1) To compare total sodium concentration (TSC) between pediatric glioma and non-neoplastic brain tissue using 23Na MRI; (2) Compare tissue conspicuity of bound sodium concentration (BSC) using 23Na MRI dual echo relative to TSC imaging. MATERIALS AND METHODS: TSC was measured in: (1) non-neoplastic brain tissues and (2) three types of manually segmented gliomas [diffuse intrinsic brainstem glioma (DIPG), recurrent supratentorial low-grade glioma (LGG), and high-grade glioma (HGG)] on sodium MRI images co-registered with proton MRI. In a subset of patients, serial changes in both TSC and BSC (dual echo 23Na MRI) were assessed for tissue conspicuity using voxel-based parametric maps. RESULTS: Twenty-six pediatric patients with gliomas (median age of 12.0 years, range 4.9 – 23.3 years) were scanned with 23Na MRI. Uninvolved tissues demonstrated a range of TSC values similar to published adult values. DIPG treated with RT demonstrated higher TSC values than the uninvolved infratentorial tissues (P&amp;lt;0.001). Recurrent supratentorial LGG and HGG exhibited higher TSC values than the uninvolved white matter (WM) and gray matter (GM) (P&amp;lt;0.002 for LGG, and P&amp;lt;0.02 for HGG). The dual echo 23Na MRI suppresses the sodium signal within both CSF and necrotic foci, resulting in improved conspicuity of both non-neoplastic and neoplastic, compared to serial TSC imaging. CONCLUSION: Quantitative 23Na MRI of pediatric gliomas demonstrates a range of values that are higher than non-neoplastic tissues. Dual echo 23Na MRI of BCS improves tissue conspicuity relative to TSC imaging. Future studies are needed to determine the value of 23Na MRI in delineating therapeutic responses in pediatric gliomas.
MEDB-70. Metabolism mediated radiation resistance in MYC-driven Medulloblastoma
Authors: Bethany Veo, Andrew Goodspeed, Eric Prince, Sujatha Venkataraman, Rajeev Vibhakar
Journal: Neuro-Oncology (2022)

Abstract Medulloblastoma (MB) is the most prevalent malignant brain tumor in children and demonstrates a high level of heterogeneity. Treatment for MB includes chemotherapy and radiation often resulting in long-term morbidity. MYC-driven MB, are high-risk tumors with poor long-term survival and increased susceptibility to develop recurrent tumors. Recurrent MB is far more aggressive with limited treatment options leading to a 5-year survival rate of 12%. To understand what drives MYC-amplified MB relapse we performed single-cell RNA sequencing of irradiated MB xenograft tumors. We identified an overall enhancement of metabolic activity in radiation-resistant cells. We further observe enhanced wild-type IDH1 and IDH2 expression in two clusters, which coincide with hypoxia and Nestin expression, marking a stem-cell like niche. Stem-like cancer cells are notoriously resilient against radiation therapy. Furthermore, wtIDH1 and IDH2 represent a unique target in radiation-resistant MB which has not previously been identified. Wild type IDH1/IDH2 are more recently shown to promote tumor proliferation and mediate metabolic reprogramming through the production of oncometabolites and substrates that functionally alter chromatin structure and gene transcription. We hypothesized that MYC modulation of wtIDH1/IDH2 facilitates metabolic reprogramming and promotes radiation-resistant cell populations. We show the change in the structural integrity of chromatin altered in radiation-resistant MB by metabolic adaptation and the effect of disrupting IDH1/IDH2 activity. We further compare these results to the chromatin profile of patient primary and matched relapsed MB samples at the single-cell level. We demonstrate that targeting IDH1/2 with chemical inhibitors suppresses MB cell growth. Our results disclose insights into the development of radiation resistance and provide a potential therapeutic target for the treatment of relapsed MYC-MB.
The genomic landscape of <i>SMARCA4</i> and the clinical characteristics in Chinese NSCLC patients.
Authors: Renhua Guo, Jun Li, Jiali Xu, Yuange He, Wei jie Sun
Journal: Journal of Clinical Oncology (2022)

e21010 Background: The tumor suppressor gene SMARCA4 encodes a submit of SWI/SNF chromatin remodeling complexes and inactivated by mutations or other mechanisms. Previous studies have reported the genomic landscape of SMARCA4 and the clinical impact in Caucasian population, but the molecular and clinical characteristics in Chinese NSCLC patients have never reported. Herein, we explore the SMARCA4 profiles in Chinese population. Methods: A total of 740 patients of NSCLC with paired tumor-normal samples were collected into the study, all samples were detected by DNA based sequencing with a 1021 gene panel. Results: The incidence of SMARCA4 mutation in Chinese NSCLC patients was 7.16% (53/740), the top10 co-mutated genes were TP53, LRP1B, KEAP1, EGFR, KRAS, HGF, FGFR1, FAT1, CDKN2A, STK11. The SMARCA4 alterations were divided to functional or unfunctional mutations according to the OncoKB database (developed by MSKCC), then we compared the clinical characteristics among the SMARCA4-functional (S-F), SMARCA4-unfunctional (S-UNF) and SMARCA4-wide type (S-WT) patients. The results showed the S-F group tended to have more Male patients (88% vs. 64% vs. 55%, p = 0.004) and more smokers (68% vs. 46% vs. 34%, p = 0.015), meanwhile the age and histopathological subtype showed no significant difference among the three groups. We also analyzed the mutation burden characteristics, The S-F group have more somatic mutations (19.20 vs. 16.29 vs. 9.06, p &lt; 0.0001) and higher TMB value (15.67 vs. 12.20 vs.5.61, p &lt; 0.0001), indicating the patients may have more clinical benefits from immunotherapy. As recent studies revealed the SMARCA4 alterations associated with a very poor prognosis in NSCLC, according to our results, the immunotherapy may be an alternative strategy, and this need more clinical explorations. Conclusions: The patients with SMARCA4-functional mutations were associated with Male and smoker in Chinese population and tended to have more somatic mutations and higher TMB value, thus may benefit more from immunotherapy.
International approaches to head and neck cancer multidisciplinary tumor board.
Authors: Christopher MKL Yao, Sydney Beatty, Anshu Giri, Jeffrey Chang-Jen Liu, Jessica R Bauman, Erich M. Sturgis, Thomas James Galloway, John A. Ridge
Journal: Journal of Clinical Oncology (2022)

e18615 Background: Multidisciplinary tumor boards are widely accepted as vehicles for improving patient outcomes in Head and Neck Cancer (HNC). Little work describes their structure and practices. The purpose of this study is to better understand the international practice patterns of multidisciplinary HNC tumor boards. Methods: A cross-sectional survey on head and neck cancer multidisciplinary tumor board practice patterns was developed by a panel of six experts and distributed internationally to HNC providers. The survey interrogated the attendance, participation, operation, and perceptions of multidisciplinary tumor conferences, through a mix of Likert-based, tick box and open-ended questions. Results: One hundred and twenty-three responses (55%) were received from 88 surgical oncologists, 17 radiation oncologists, and 18 medical oncologists from nine different countries. Overall, most HNC tumor boards are led by a surgeon (77%), and most commonly 5-10 minutes (61%) was spent on each case. In 60% of responses, all HNC patients were discussed at their tumor boards, while select cases were presented in 40% of responses. Pathology was routinely reviewed in 75% of sites and imaging reviewed in 95% of sites. In 75% of responses, sufficient time was felt to be spent on each case. Majority (75%) of tumor boards documented their recommendation, with 92% reporting that inability to reach a consensus recommendation was rare. When this occurred, the most common recourse was involving patient decision making (53%), followed by offline discussion until an agreement is reached (38%). Most respondents felt that tumor boards rarely altered the treatment plan (68%), while 37% felt the treatment plan was sometimes altered. Involvement of radiation and medical oncology prior to surgery varied, with 53% sending patients routinely, 32% sometimes, and 15% deferring referral. Logistics was cited as a primary barrier. Surgeons and radiation oncologists agree that the top three reasons tumor boards assist in cancer care are: receiving additional opinion and perspective, coordinating care, and communication. Medical oncologist also found tumor boards enhance clinical trial enrollment. Conclusions: While there are variations in the structure and process of multidisciplinary tumor boards, the majority of management is agreed upon by the treatment team. Areas of improvement include verification of cancer stage, identifying logistics that prevent timely and documentation of recommendations. Identifying the variations from most-common practice should provide a mechanism for improvement.
SURG-07. The impact of early targeted therapy on the neurosurgical approach to pediatric low-grade glioma
Authors: Gianluca Piatelli, Marco Pavanello, Gianluca Piccolo, Andrea Rossi, Maria Luisa Garrè, Patrizia De Marco, Valentina Iurilli, Manila Antonelli, Gabriele Gaggero, Samuele Caruggi, Antonio Verrico, Marco Crocco, Claudia Milanaccio
Journal: Neuro-Oncology (2022)

Abstract We report two cases of pediatric low-grade glioma (pLGG) treated with vemurafenib, an oral BRAF-inhibitor: a 12-year-old girl with involvement of basal ganglia, hypothalamus, and diencephalic junction; a 3-year-old boy, with an optic pathway/hypothalamic glioma extending along the left optic tract and basal ganglia. Both received a biopsy and molecular analysis was performed in the girl’s tumor, showing BRAF V600E mutation. Therefore, instead of surgical removal planned by neurosurgeons, first-line treatment with vemurafenib was started: after one month 45% reduction of the mass according to RANO criteria was found, as well as better balance control and strong reduction of the right arm paresis; five months later, a 70% shrinkage was detected, stabilized to 76% after a year. The young boy first started chemotherapy with vincristine and carboplatin, but at the end of the induction phase the tumor had increased and ascites, hydrocephalus, and visual impairment occurred. Molecular testing showing BRAF V600E mutation on the initial tumor biopsy was obtained; therefore, the surgical option was postponed and therapy with vemurafenib started. After only three days, visual acuity and muscle tone improved; brain MRI showed a 34% reduction of the mass after one week, increased up to 65% after six months. Therefore, no ulterior surgery was necessary. In pLGG, the neurosurgical biopsy is essential to let an early and rapid molecular diagnosis of BRAF mutations and guide subsequent targeted therapies. Our cases demonstrate how a prompt radiological response to vemurafenib and the related clinical improvement can influence both therapeutic and surgical decisions, hopefully reducing the occurrence of second neurosurgery with associated risks of neurological sequelae. To our knowledge, this is the first report assessing such a quick shrinkage in pLGG treated with vemurafenib, highlighting the importance of an early investigation of BRAF status in all cases of LGG in children.
Mycobacterial infections in adults with haematological malignancies and haematopoietic stem cell transplants: guidelines from the 8th European Conference on Infections in Leukaemia
Authors: Anne Bergeron, Malgorzata Mikulska, Julien De Greef, Louise Bondeelle, Tomas Franquet, Jean-Louis Herrmann, Christoph Lange, Isabel Spriet, Murat Akova, J Peter Donnelly, Johan Maertens, Georg Maschmeyer, Montserrat Rovira, Delia Goletti, Rafael de la Camara, Hildegard Greinix, Johan Maertens, Julien De Greef, Monica Slavin, Isabel Spriet, Petr Hubacek, Anne Bergeron, Catherine Cordonnier, Jukka Kanerva, Raoul Herbrecht, Jean-Louis Herrmann, Fanny Lanternier, Louise Bondeelle, Christine Robin, Hermann Einsele, Thomas Lehrnbecher, Andreas Groll, Georg Maschmeyer, Christoph Lange, Marie von Lilienfeld-Toal, Dorothea Pana, Emmanuel Roilides, Csaba Kassa, Diana Averbuch, Dan Engelhard, Simone Cesaro, Malgorzata Mikulska, Livio Pagano, Elio Castagnola, Francesca Compagno, Delia Goletti, Alessio Mesini, Peter J Donnelly, Jan Styczynski, Aida Botelho de Sousa, Mahmoud Aljurf, Rafael de la Camara, David Navarro, Montserrat Rovira, Tomas Franquet, Carol Garcia-Vidal, Per Ljungman, Karlis Paukssen, Roland Ammann, Frédéric Lamoth, Hans Hirsch, Nicole Ritz, Murat Akova, Mansour Ceesay, Adilia Warris, Roy Chemaly
Journal: The Lancet Infectious Diseases (2022)
Effect of mevalonate pathway inhibitors on outcomes of patients (pts) with HER2-positive early breast cancer (BC) in the ALTTO trial.
Authors: Carmine De Angelis, Jamunarani Veeraraghavan, Vidyalakshmi Sethunath, Lieveke Ameye, Marianne Paesmans, Sarra El-Abed, Anup Choudhury, Sylvia Napoleone, Saranya Chumsri, Martine J. Piccart-Gebhart, Alvaro Moreno-Aspitia, Henry Leonidas Gomez, Giuseppe Viale, Susan G. Hilsenbeck, Mothaffar F. Rimawi, C. Kent Osborne, Evandro de Azambuja, Rachel Schiff
Journal: Journal of Clinical Oncology (2022)

522 Background: Our preclinical findings suggest a role for the mevalonate pathway (MVA) in treatment resistance in HER2+ BC by providing alternative growth and survival signaling to bypass potent HER2 blockade, which could be overcome by the MVA inhibitors statins and nitrogen-containing bisphosphonates (NBs). Here we explored the effect of MVA inhibitors’ use on pts’ outcomes in the ALTTO trial (BIG2-06; NCT00490139). Methods: In the ALTTO trial, 8381 pts with HER2+ BC were randomized to 1 year of adjuvant lapatinib (L), trastuzumab (T), L+T, or T→L. All pts with documented treatment start with statins or NBs &lt; 1 year after randomization were considered as MVA inhibitors users. Survival curves, with a median follow-up of 6.9 years, for disease-free survival (DFS), distant relapse-free interval (DRFI), BC-specific survival (BCSS), and overall survival (OS) according to MVA inhibitors use were estimated by the Kaplan Meier method and Log-rank test. All multivariate survival analyses employed a Cox proportional hazards regression model, adjusting for tumor size, nodal status, hormonal receptor (HoR), menopausal status, BMI, timing of chemo, and randomization arm. We considered interactions terms in Cox’s model between MVA inhibitors use and randomization arm, hormonal status, and BMI group. Results: Among the 8381 pts included in this study, 493 and 299 were statins or NBs users, respectively. Table 1 summarizes the significant differences in pts’ characteristics according to MVA inhibitors use ( P &lt;.005). In multivariate survival analyses, only NBs use was associated independently with better BCSS (HR, 0.44; 95% CI, 0.23 - 0.84; P = 0.014). Statin use was not independently associated with prognosis but only in interaction with pts characteristics: worse DFS, BCSS and OS in pts treated with L+T, worse DRFI and OS in pts treated with HoR+ BC (respective interaction P-values &lt;0.05 in the Cox’s model). Conclusions: NBs independently predicted improved BC-specific outcome in pts with HER2+ BC treated with adjuvant anti-HER2 therapy. Statin use was associated with an inferior outcome in pts with HoR+ disease and/or those treated with L+T. Whether this inferior association in statin users may reflect the underlying predisposition factors that can weaken the efficacy of anti-HER2 treatments and whether this effect was observed only in the L+T arm due to the more potent inhibition of the HER2 signaling pathway remain open questions. Further clinical investigations on the impact of MVA inhibitors on the outcome of pts with HER2+ BC are warranted. [Table: see text]